Colocalized white matter plasticity and increased cerebral blood flow mediate the beneficial effect of cardiovascular exercise on long-term motor learning

Cardiovascular exercise (CE) is a promising intervention strategy to facilitate cognition and motor learning in healthy and diseased populations of all ages. CE elevates humoral parameters, such as growth factors, and stimulates brain changes potentially relevant for learning and behavioral adaptations. However, the causal relationship between CE-induced brain changes and human's ability to learn remains unclear. We tested the hypothesis that CE elicits a positive effect on learning via alterations in brain structure (morphological changes of gray and white matter) and function (functional connectivity and cerebral blood flow in resting state). We conducted a randomized controlled trial with healthy male and female human participants to compare the effects of a 2 week CE intervention against a non-CE control group on subsequent learning of a challenging new motor task (dynamic balancing; DBT) over 6 consecutive weeks. We used multimodal neuroimaging [T1-weighted magnetic resonance imaging (MRI), diffusion-weighted MRI, perfusion-weighted MRI, and resting state functional MRI] to investigate the neural mechanisms mediating between CE and learning. As expected, subjects receiving CE subsequently learned the DBT at a higher rate. Using a modified nonparametric combination approach along with multiple mediator analysis, we show that this learning boost was conveyed by CE-induced increases in cerebral blood flow in frontal brain regions and changes in white matter microstructure in frontotemporal fiber tracts. Our study revealed neural mechanisms for the CE–learning link within the brain, probably allowing for a higher flexibility to adapt to highly novel environmental stimuli, such as learning a complex task. SIGNIFICANCE STATEMENT It is established that cardiovascular exercise (CE) is an effective approach to promote learning and memory, yet little is known about the underlying neural transfer mechanisms through which CE acts on learning. We provide evidence that CE facilitates learning in human participants via plasticity in prefrontal white matter tracts and a colocalized increase in cerebral blood flow. Our findings are among the first to demonstrate a transfer potential of experience-induced brain plasticity. In addition to practical implications for health professionals and coaches, our work paves the way for future studies investigating effects of CE in patients suffering from prefrontal hypoperfusion or white matter diseases